4,4'-Diaminodiphenylsulfone

Toxicity

Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary.

Chemical properties

Off -White Crystalline Solid

The Uses of 4,4'-Diaminodiphenylsulfone

4,4'-diaminodiphenylsulfone, an antibacterial used in the treatment of dermatitis herpetiformis, can be used for preparation polyimide and epoxy resin material.

Background

4,4'-Diaminodiphenylsulfone is a sulfone active against a wide range of bacteria but mainly employed for its actions against mycobacterium leprae. Its mechanism of action is probably similar to that of the sulfonamides which involves inhibition of folic acid synthesis in susceptible organisms. It is also used with pyrimethamine in the treatment of malaria. 

Definition

ChEBI: A sulfone that is diphenylsulfone in which the hydrogen atom at the 4 position of each of the phenyl groups is substituted by an amino group. It is active against a wide range of bacteria, but is mainly employed for its actions against Mycobacteriu leprae, being used as part of multidrug regimens in the treatment of all forms of leprosy.

Indications

Although dapsone (Avlosulfon) was once used in the treatment and prophylaxis of chloroquine-resistant P. falciparum malaria, the toxicities associated with its administration (e.g., agranulocytosis, methemoglobinemia, hemolytic anemia) have severely reduced its use. Occasionally dapsone has been added to the usual chloroquine therapeutic regimen for the prophylaxis of chloroquine-resistant P. falciparum malaria. It is also used in combination therapy for leprosy.

Manufacturing Process

p-Chloronitrobenzene is reacted with NaSO2C6H5NHCOCH3 to give as an intermediate, O2NC6H5SO2C6H5NHCOCH3 which is then reduced and deacetylated to give the product, dapsone. Alternatively, benzene and sulfuric acid react to give phenyl sulfone which is nitrated, then reduced to give dapsone.

Antimicrobial activity

Dapsone is active against many bacteria and some protozoa. Fully susceptible strains of M. leprae are inhibited by a little as 0.003 mg/L. It is predominantly bacteristatic. Resistance is associated with mutations in the folP1 gene involved in the synthesis of para-aminobenzoic acid.

Acquired resistance

Resistance to high levels is acquired by several sequential mutations. As a result of prolonged use of dapsone monotherapy, acquired resistance emerged in patients with multibacillary leprosy in many countries. Initial resistance also occurs in patients with both paucibacillary and multibacillary leprosy. Thus, leprosy should always be treated with multidrug regimens. Resistance of M. leprae to dapsone (and other anti-leprosy drugs) may now be determined by use of DNA microarrays.

Reactivity Profile

4,4'-Diaminodiphenylsulfone can neutralize acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated in combination with strong reducing agents, such as hydrides. Incompatible with strong oxidizing agents. Also incompatible with epoxy resins under uncontrolled conditions .

Pharmacokinetics

Dapsone is a sulfone with anti-inflammatory immunosuppressive properties as well as antibacterial and antibiotic properties. Dapsone is the principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy. As an anti-infective agent, it is also used for treating malaria and, recently, for Pneumocystic carinii pneumonia in AIDS patients. Dapsone is absorbed rapidly and nearly completely from the gastrointestinal tract. Dapsone is distributed throughout total body water and is present in all tissues. However, it tends to be retained in skin and muscle and especially in the liver and kidney: traces of the drug are present in these organs up to 3 weeks after therapy cessation.

Clinical Use

Dapsone is approved for the treatment of an autoimmune blistering skin disease, dermatitis herpetiformis. This intensely pruritic eruption is characterized histologically by a dense dermal infiltration of neutrophils and subepidermal blisters. Other skin diseases in which dapsone is helpful are linear immunoglobulin A (IgA) dermatosis, subcorneal pustular dermatosis, leukocytoclastic vasculitis, and a variety of rarer eruptions in which neutrophils predominate, including some forms of cutaneous lupus erythematosus.

Side Effects

Although usually well tolerated at standard doses, gastrointestinal upsets, anorexia, headaches, dizziness and insomnia may occur. Less frequent reactions include skin rashes, exfoliative dermatitis, photosensitivity, peripheral neuropathy (usually in non-leprosy patients), tinnitus, blurred vision, psychoses, hepatitis, nephrotic syndrome, systemic lupus erythematosus and generalized lymphadenopathy.
The term ‘dapsone syndrome’ is applied to a skin rash and fever occurring 2–8 weeks after starting therapy and sometimes accompanied by lymphadenopathy, hepatomegaly, jaundice and/or mononucleosis.
Blood disorders include anemia, methemoglobinemia, sulfhemoglobinemia, hemolysis (notably in patients with glucose- 6-phosphate dehydrogenase deficiency), mononucleosis, leukopenia and, rarely, agranulocytosis. Severe anemia should be treated before patients receive dapsone.
The incidence of adverse reactions declined in the 1960s but reappeared around 1982 when multidrug therapy was introduced, and may represent an unexplained interaction with rifampicin.

Safety Profile

Poison by ingestion, intraperitoneal, and subcutaneous routes. Human systemic effects by ingestion: agranulocytosis, change in tubules and other kidney changes, cyanosis, effect on joints, hemolysis with or without anemia, jaundice, methemoglobinemiacarboxyhemoglobinemia, retinal changes, somnolence. Experimental reproductive effects. Can cause hepatitis, dermatitis, and neuritis. Questionable carcinogen with experimental carcinogenic and neoplastigenic data. Human mutation data reported. Used in leprosy treatment and veterinary medicine. When heated to decomposition it emits very toxic fumes of NOx and SOx. 

Drug interactions

Potentially hazardous interactions with other drugs
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid.

Metabolism

Dapsone undergoes enterohepatic recycling. Dapsone is acetylated to monoacetyldapsone, the major metabolite, and other mono and diacetyl derivatives. Acetylation shows genetic polymorphism. Hydroxylation is the other major metabolic pathway resulting in hydroxylamine dapsone, which may be responsible for dapsoneassociated methaemoglobinaemia and haemolysis. Dapsone is mainly excreted in the urine, only 20% of a dose as unchanged drug.